Severe malarial anemia (SMA) is the most common clinical manifestation of severe malaria in infants and young children and causes ~ 20% mortality in children <3 years in areas holoendemic for P. falciparum. SMA is a multifactorial disease involving increased erythrocyte destruction as well as decreased erythrocyte production. Although the etiology of these mechanisms likely involves dysregulation in inflammatory mediators, the underlying molecular basis of SMA remains largely undefined. The current application is a competing continuation of a previously funded proposal in response to an RFA to meet this challenge. To gain improved understanding of the factors that regulate SMA, we have taken a genetic-based approach that investigates the role of innate inflammatory mediators in conditioning the development and outcomes of SMA in children residing in a holoendemic area of malaria transmission in western Kenya. Our previous application focused on defining the complex phenotype of SMA by performing extensive clinical evaluations so that the underlying genes responsible for the varied outcomes could be established. These investigations identified a number of novel inflammatory mediators and polymorphisms within immune response genes associated with susceptibility to SMA. These studies further revealed that HIV-1 exposure significantly enhanced the development of SMA during acute malaria. This finding has important public health implications since 20% of the study participants were exposed to HIV-1, a rate comparable to that throughout much of sub-Saharan Africa. Although we successfully defined factors that promote SMA, these studies were limited due to small sample volumes available from severely anemic children. Recent advances in biotechnology now allow for cost-effective, high-throughput genetic and immunological analyses that overcome these limitations. Since malaria is a polygenic disease, exploration of a larger panel of genes is required to successfully identify those variants that condition clinical outcomes. As such, in the competing continuation, we will investigate a comprehensive, but focused panel of innate immune response genes we hypothesize to be important in conditioning acute and longitudinal outcomes of SMA. This will allow for construction of haplotypes which appear to be better predictors of complex disease outcomes than individual polymorphisms. The primary goals of this proposal are: 1) to determine the genotypic profiles and haplotypic structures that condition the development and outcomes of SMA in children with malaria as a single disease and in children exposed to HIV-1, and 2) to identify innate immune response genes that mediate protective immunity against SMA following repeated episodes of malaria. The overall goal of this proposal is to identify critical genes that underlie susceptibility to SMA. Successful accomplishment of this goal will aid in identifying those children in which targeted therapeutic interventions are required.